Browsing by Subject "IL-6"
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Item Mechanism of local IL-6 production and its role in accelerating vascular inflammation leading to aortic diseases(2008-12-03) Brian Cuong Tieu; Ronald Tilton; Steven Weinman; Michael Boulton; Dianna Milewicz; Darrell CarneyVascular inflammation plays a significant role in aortic diseases and involves enhanced recruitment and local activation of circulating monocytes along with cytokine production, but the mechanisms responsible for these processes are unclear. The cytokine interleukin-6 (IL-6) is highly induced in aortic aneurysm and dissection and significantly increases the risk of aneurysm rupture and mortality due to cardiovascular diseases; however, it remains unknown where and how IL-6 is produced in the vascular wall and how it contributes to disease exacerbation. Using an Ang II-infusion mouse model, we found that 6 days of subcutaneous Ang II infusion into aged C57BL/6J mice induced aortic IL-6 and MCP-1 predominantly in the tunica adventitia. Likewise, IL-6 was detected mostly in the adventitia of sporadic aortic dissections in humans. There was concomitant macrophage recruitment, adventitial expansion, and development of thoracic and suprarenal aortic aneurysms and dissections in treated wild-type mice. In contrast, no dissections were produced with infusion into IL-6-/- or CCR2-/- mice over the same time period along with significantly reduced inductions of aortic IL-6 and MCP-1. Using flow cytometric quantification of aortic cellular constituents, we found that Ang II induced CCR2+ macrophage accumulation of a specific CD14hiCD11bhiF4/80- phenotype selectively in aortic dissections and not in aortas from IL-6-/- mice, which were CD14loCD11bloF4/80+. Adoptive transfer of CCR2+/+ monocytes into CCR2-/- mice resulted in selective monocyte uptake into the thoracic and suprarenal aorta with restoration of IL-6 and MCP-1 secretion and increased incidence of dissection. To elucidate a source of IL-6, we demonstrated that aortic adventitial fibroblasts (AoAFs) highly produce IL-6 and MCP-1 and Ang II treatment increased their expression. Ang II and monocytes stimulated AoAF proliferation also. In addition, coculture of monocytes and AoAFs strongly potentiated MCP-1 and IL-6, which differentiated monocytes to macrophages and up-regulated CD14 and CD11b as well as induced MCP-1 and MMP-9 expression. These results suggest that AoAFs are a source of IL-6 and that a leukocyte-fibroblast interaction in the aortic adventitia potentiates its production, leading to promotion of local monocyte recruitment and activation, thereby accelerating vascular inflammation, ECM remodeling and aortic destabilization.Item STAT3-protein interactions in IL-6/gp130 signaling(2008-08-20) TIEYING HOU; John Papaconstantinou; kishor bhakat; John DiGiovanni; Istvan Boldogh; chunming Liu; Allan BrasierThe Signal Transducer and Activator of Transcription 3 (STAT3) is a central transcription factor downstream of IL-6/gp130 signaling. This thesis investigates how STAT3 regulates IL-6 signal transduction by interacting with its coactivators. First, the function of an IL-6 inducible complex of STAT3 with cyclin-dependent kinase 9 (CDK9) was examined by using gamma-Fibrinogen (ã-FBG), an acute phase protein, as a model. IL-6 induces a strong nuclear association of STAT3 with CDK9, which is mediated via both STAT’s NH2-terminal and COOH-terminal domains. The induction of ã-FBG by IL-6 is significantly decreased when CDK9 is repressed by kinase inhibitor or downregulated by siRNA. Moreover, an IL-6-inducible STAT3 and CDK9 binding to the proximal ã-FBG promoter is observed. This phenomenon is accompanied by increased loading of RNA Pol II and phospho-Ser2 CTD Pol II on the ã-FBG TATA box and coding regions. Finally, both IL-6-inducible RNA Pol II and phospho-S2 CTD RNA Pol II association with the endogenous ã-FBG gene are significantly decreased when CDK9 kinase activity is inhibited. In this study we provide evidence that activated STAT3 regulates the transcription elongation of the ã-FBG gene by associating with CDK9. The magnitude of IL-6/gp130 signaling is also regulated by p300, another coactivator of STAT3 with histone acetyltransferase activity (HAT). The p300-STAT3 interaction is partially regulated by the STAT3 NH2-terminal domain. The second part of this thesis investigates the STAT3 NH2-terminal function and how its interaction with p300 regulates STAT3 signal transduction. The STAT3 NH2-terminal domain is required for the downstream gene expression, including socs3, c-fos and p21. Additionally, the recruitment of p300 and RNA Pol II to the socs3 promoter is reduced in MEFs stably expressing STAT3-DN mutant which is deficient in the NH2-terminal domain. We also reported that the binding site of the STAT3 NH2-terminal domain maps to the p300 bromodomain and the STAT3 NH2-terminal acetylation induced by p300 stabilizes this interaction. Finally, the deletion of p300 bromodomain not only reduces its binding affinity to STAT3 but also inhibits its association to the socs3 promoter. Our data indicates that the STAT3 NH2-terminal domain regulates gp130 signaling by interacting with the p300 bromodomain, thereby stabilizing enhanceosome assembly. In summary, my thesis work has described a mechanism by which the STAT3 NH2-terminal domain controls gene expression by interacting with coactivators and transcriptional elongation factors. The multiple functions of the STAT3 NH2-terminal domain make it a potential target for the therapeutic modulation in inflammatory disease.Item The Impact of Social Stress on Central Nervous System Inflammation and T Cell Response to Theiler?s Virus Infection(2012-07-16) Vichaya, Elisabeth GoodA growing body of evidence suggests that social stress contributes to the pathogenesis of neurodegenerative diseases, such as multiple sclerosis (MS). For example, prior research has shown that social disruption (SDR) stress behaviorally and immunologically exacerbates Theiler?s murine encephalomyelitis virus (TMEV) infection. TMEV infection results in acute infection of the central nervous system (CNS) followed by a chronic demyelinating autoimmune disease, similar to that seen in MS. Research suggests that social stress exerts these effects by altering the immune response to infection. More specifically, it is hypothesized that SDR sensitizes the acute inflammatory response to infection and suppresses T cell effector function in the acute phase of disease. It was demonstrated that SDR is sufficient to alter inflammation. Exposure to a single session of SDR increases IL-??1? mRNA expression; however, IL-??6 mRNA expression, but not IL-??1?, is up regulated in response to chronic SDR. Furthermore, chronic SDR prior to infection resulted in increased infection related central IL-??6 and IL-??1? mRNA expression, and central administration of IL-??6 neutralizing antibody during SDR reverses this increase in neuroinflammation. This suggests that SDR sensitizes infection related CNS inflammation through an up-??regulation of IL-??6. Chronic SDR prior to infection also resulted in enhanced CNS viral titers and suppression of virus-??induced CD4 and CD8 T cell IFN-??? release within the CNS. As a whole, this research indicates that SDR exacerbates the disease course of TMEV infection by altering the central innate and adaptive immune response to infection. This research enhances our understanding of the mechanisms by which social stress exacerbates neurodegenerative disease pathogenesis.